Targeting Decidual Macrophage Polarization through JNK Signaling Pathway Inhibition Alleviates Adverse Pregnancy...

Early spontaneous abortion (ESA) is associated with abnormal decidual macrophage polarization at the maternal-fetal interface. While JNK signaling is recognized in implantation and immunomodulation, its contribution to decidual macrophage polarization in the ESA is poorly understood. The decidual tissues of ESA patients were collected to detect the polarization status and the expression of JNK1/2 and p-JNK in decidual macrophages (DMs) through flow cytometry assessment. PMA-induced THP-1 cell differentiation into macrophage phenotypes in vitro. To enhance our knowledge of macrophage polarization, activation of M1 macrophages was achieved using LPS and IFN-γ, while activation of M2 macrophages was accomplished using IL-4 and IL-13, followed by treatment with varying concentrations of the JNK inhibitor (SP600125) to see how it affected the balance between the two macrophage types. The impact of the JNK signaling pathway on macrophage polarization and pregnancy outcomes in spontaneous abortion mouse models was assessed. Our findings revealed enhanced M1 polarization and dysregulated JNK phosphorylation in decidual macrophages from ESA patients. Inhibition of the JNK by SP600125 shifted macrophage differentiation toward the M2 phenotype, enhancing production of TGF-β and IL-10. Concurrently, it inhibited M1 macrophage polarization, lessening inflammatory mediator secretion, notably TNF-α and IL-6. Furthermore, blocking the JNK signaling pathway significantly increased the M2 phenotype of DMs and reduced the resorption rate of mouse embryos. The current study elucidated that blocking the JNK signaling pathway suppressed the pro-inflammatory polarization in macrophages, thereby attenuating the adverse pregnancy outcomes of ESA.